CORRESPONDENCE: LETTER TO THE EDITOR
Prevention of Atrial Fibrillation by Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers
Christopher J. Boos, MBBS, MRCP* and
Gregory Y.H. Lip, MD, FRCP, FESC, FACC
* Haemostasis, Thrombosis, and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH, United Kingdom (Email: christopherboos{at}hotmail.com).
We read with great interest the report by Healey et al. (1) in which they presented a meta-analysis of published randomized trials involving the prevention of atrial fibrillation (AF) with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs). The investigators present a number of highly plausible hypotheses to explain the potential mechanisms by which the renin-angiotensin-aldosterone system (RAAS) blockade with these agents might reduce the burden of AF, such as antiarrhythmic effects and reversed cardiac remodeling by left ventricular hypertrophy regression and reduced left atrial stretch.
We would like to offer additional pathophysiological insights into the benefits of these drugs on AF and its complications. First, there is mounting evidence to support an association between inflammation and AF. For example, atrial biopsies taken from patients in AF have demonstrated evidence of inflammatory infiltrates within the atrial tissue (2,3). Furthermore, consistent links exist between inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor-alpha (TNF- ), interleukin (IL)-6, white cell count, and the presence/development of AF. It is also clear that angiotensin (ang) II has several proinflammatory properties (4). For example, ang II can act locally as a chemokine and inflammatory molecule, increasing the production of several proinflammatory cytokines (e.g., IL-6 and TNF-), adhesion molecules (such as vascular cell adhesion molecule-1 [VCAM-1] on endothelial cells, intracellular adhesion molecule [ICAM]-1 and osteopontin, a known macrophage chemotactic and adhesion molecule), chemoattractant protein (MCP)-1 (further increasing monocyte recruitment), and various selectins (such as P-selectin and s-selectin, leading to leukocyte tethering and rolling) (5–8).
There is also histological evidence to confirm that AF (both persistent and paroxysmal) can lead to increased ang II receptor expression (9). In a key study, Cardin et al. were able to link increased atrial expression of ang II receptors with increased atrial cell death and leukocyte infiltration, again supporting a potential link among the RAAS, inflammation, and AF (10). It would also appear that the relationship between ang II and inflammation is reciprocal, as not only does ang II cause inflammation, but the converse is also true with inflammation itself acting as a stimulus for increased ang II production.
Moreover, RAAS blockade influences the complications associated with AF; also, AF confers a hypercoagulable state, even in the absence of underlying heart disease; abnormalities of hemostasis, fibrinolysis, endothelium, and platelets have all been described in this arrhythmia, which may increase the risk of stroke and thromboembolism (11). Furthermore, there is an established link among inflammation, AF, and thrombosis (12). Indeed, ang II has known prothrombotic properties, and in the AF substudy of the Losartan Intervention For End Point Reduction in Hypertension (LIFE) trial, a significant reduction occurred in stroke among losartan- versus atenolol-treated AF patients, despite equivalent blood pressure reduction (13).
Finally, there appears to be prevailing links between AF and inflammation, thrombosis, and angiotensin II activation. Consequently, RAAS blockade (by ACEIs and ARBs), with subsequent reduction in AF burden and its complications, is consistent with the reduction in the inflammatory and prothrombotic substrate related to AF.
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1. Healey JS, Baranchuk A, Crystal E, et al. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockersa meta-analysis. J Am Coll Cardiol 2005;45:1832-1839.[Abstract/Free Full Text]2. Mihm MJ, Yu F, Carnes CA, et al. Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation Circulation 2001;104:174-180.[Abstract/Free Full Text] 3. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A. Histological substrate of atrial biopsies in patients with lone atrial fibrillation Circulation 1997;96:1180-1184.[Abstract/Free Full Text] 4. Engelmann MD, Svendsen JH. Inflammation in the genesis and perpetuation of atrial fibrillation Eur Heart J 2005;26:2083-2092.[Abstract/Free Full Text] 5. Zhao Q, Ishibashi M, Hiasa K, et al. Essential role of vascular endothelial growth factor in angiotensin II-induced vascular inflammation and remodeling Hypertension 2004;44:264-270.[Abstract/Free Full Text] 6. Tamarat R, Silvestre JS, Durie M, Levy BI. Angiotensin II angiogenic effect in vivo involves vascular endothelial growth factor- and inflammation-related pathways Lab Invest 2002;82:747-756.[Web of Science][Medline] 7. Ishibashi M, Hiasa K, Zhao Q, et al. Critical role of monocyte chemoattractant protein-1 receptor CCR2 on monocytes in hypertension-induced vascular inflammation and remodeling Circ Res 2004;94:1203-1210.[Abstract/Free Full Text] 8. Psychari SN, Apostolou TS, Sinos L, et al. Relation of elevated C-reactive protein and interleukin-6 levels to left atrial size and duration of episodes in patients with atrial fibrillation Am J Cardiol 2005;95:764-767.[CrossRef][Web of Science][Medline] 9. Goette A, Staack T, Rocken C, et al. Increased expression of extracellular signal-regulated kinase and angiotensin-converting enzyme in human atria during atrial fibrillation J Am Coll Cardiol 2000;35:1669-1677.[Abstract/Free Full Text] 10. Cardin S, Li D, Thorin-Trescases N, Leung TK, Thorin E, Nattel S. Evolution of the atrial fibrillation substrate in experimental congestive heart failureangiotensin-dependent and -independent pathways. Cardiovasc Res 2003;60:315-325.[Abstract/Free Full Text] 11. Lip GYH. Does atrial fibrillation confer a hypercoagulable state? Lancet 1995;346:1313-1314.[CrossRef][Web of Science][Medline] 12. Conway DS, Buggins P, Hughes E, Lip GY. Relationship of interleukin-6 and C-reactive protein to the prothrombotic state in chronic atrial fibrillation J Am Coll Cardiol 2004;43:2075-2082.[Abstract/Free Full Text] 13. Watchell K, Lehto M, Gerdts E, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenololthe Losartan Intervention for End Point Reduction in Hypertension (LIFE) study. J Am Coll Cardiol 2005;45:712-719.[Abstract/Free Full Text]
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